Originally published as JCO Early Release 10.1200/JCO.2005.02.568 on May 2 2005

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Evidence for Distinct Pathomechanisms in Genetic Subgroups of Chronic Lymphocytic Leukemia Revealed by Quantitative Expression Analysis of Cell Cycle, Activation, and Apoptosis-Associated Genes

From the Department of Internal Medicine III, University of Ulm, Ulm; Department of Molecular Genetics and Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany; Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

Address reprint requests to Stephan Stilgenbauer, Internal Medicine III, University of Ulm, Robert-Koch-Straße 8, 89081 Ulm, Germany; e-mail: stephan.stilgenbauer{at}medizin.uni-ulm.de

PURPOSE: In patients with chronic lymphocytic leukemia (CLL), the VH mutation status and genomic aberrations (13q–, +12q, 11q–, 17p–) identify distinct prognostic subgroups. The aim was to elucidate biologic mechanisms through which these genetic markers may exert their pathogenic influence.

PATIENTS AND METHODS: Twenty-four genes involved in apoptosis, cell cycle, B-cell activation, and B-cell receptor (BCR) signaling were analyzed by real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in 82 CLL cases constituting prototypic genetic CLL subgroups as defined by the VH mutation status and the genomic aberrations 13q–, +12, 11q–, and 17p–.

RESULTS: The VH mutation subgroups were characterized by a differential expression of the BCR associated genes ZAP70 and PI3K. Among the subgroups defined by genomic aberrations, there was a deregulation of candidate genes from the affected critical genomic regions such as CDK4 (up), ATM (down), and TP53 (down) in the groups +12, 11q–, and 17p–, respectively. Additionally, the genomic subgroups were characterized by a significant deregulation of cell cycle and apoptosis regulators: AKT (up) in 13q, E2F1 (up) in +12, MYC (up) and BCL-2 (down) in 17p–, and CCND3 (down) in 11q– as well as 17p–. The 17p– subgroup showed an additional down-regulation of BCR-associated genes such as SYK and PI3K.

CONCLUSION: The characteristic gene expression patterns observed implicate a differential regulation of cell cycle, apoptosis, and BCR signaling in the genetic subgroups illustrating distinct pathomechanisms and are evidence for a gene dosage effect being operative in CLL. These findings link the biologic diversity and clinical heterogeneity of CLL.

Supported by the DFG (Sti 296/1-1), Deutsche Krebshilfe (70-3183-Li1), Wilhelm Sander Stiftung (2002.095.1), Jubiläumsfonds of the Austrian National Bank (No. 9964; U.J.).

Presented at the Annual Meeting of the American Society of Hematology, San Diego, CA, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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